The broad goal of the proposed research is to determine at the single whole muscle fiber level cellular and molecular events that underlie reactions that have been observed in both aging and long-term denervated muscle. Specifically, these include 1) the time course and topography of satellite cell activation after denervation, 2) the formation of new muscle fibers alongside existing ones in both aging and denervated muscle, 3) an unusual nuclear clumping phenomenon that occurs in 7-month denervated muscle, and 4) the time course and topography of expression of important genes that from tissue-level molecular analysis appear to play an important role in the reactions of muscle fibers to both denervation and aging. The host laboratory of Dr. McLennan has studied myotube formation in the mammalian fetus, as well as molecular aspects of muscle regeneration in tissues. The proposed experiments will combine Dr. McLennan's molecular expertise with the applicant's morphological and experimental expertise, and it will bring together Dr. McLennan's experience in studying prenatal myogenesis at the cellular level with that of the applicant, who is studying neomyogenesis at the other end of the life span. The proposed research is part of a project designed to devise ways of enhancing the restorative ability of aging and denervated muscles.